Zero-order release method

ABSTRACT

A diffusible solid is released by diffusion into a fluid medium from a cavity within a container through an opening therein at a rate which is independent of the amount of solid present in the container. Zero-order release is effected by the shape of the cavity and the opening. The rate of release is related to the solubility and to the diffusion constant of the solid in the fluid medium. For a given substance, the rate of release is determined by cavity shape and dimensions of the diffusion opening. The method is adapted for use in both liquid and gaseous media and can be used for the zero-order release of drug substance into the system of a living organism, and for nonmedical uses.

United States Patent [191 Brooke Dec. 9, 1975 [73] Assignee: MeadJohnson & Company,

Evansville, Ind.

22 Filed: Nov. 26, 1974 211 Appl. No.: 527,477

Related US. Application Data [63] Continuation-impart of Ser. No.405,616, Oct. 11,

1973, Pat. NO. 3,851,648.

[52] US. Cl. 128/260; 119/25; 128/272;

239/57; 43/131 [51] Int. Cl. A61M 31/00; A61M 7/00 [58] Field of Search128/2 R, 130, 214 E, 260,

3,545,439 12/1970 Duncan 128/260 3,641,237 2/1972 Gould et a]. 128/260 X3,661,326 5/1972 Wilson 239/60 3,677,711 7/1972 Bond 239/57 X 3,851,64812/1974 Brooke 128/260 Primary ExaminerAldrich F. Medbery Attorney,Agent, or Firm-Robert H. Uloth; Robert E. Carnahan [5 7] ABSTRACT Adiffusible solid is released by diffusion into a fluid medium from acavity within a container through an opening therein at a rate which isindependent of the amount of solid present in the container. Zero-orderrelease is effected by the shape of the cavity and the opening. The rateof release is related to the solubility and to the diffusion constant ofthe solid in the fluid medium. For a given substance, the rate ofrelease is determined by cavity shape and dimensions of the diffusionopening. The method is adapted for use in both liquid and gaseous mediaand can be used for the zero-order release of drug substance into thesystem of a living organism, and for non-medical uses.

11 Claims, 6 Drawing Figures Sheet 1 of 4 US. Patent Dec. 9, 1975 U.S.Patent Dec. 9, 1975 Sheet 2 of4 3,924,622

FIGURE 3 FIGURE 4 US. Patent Dec. 9, 1975 Sheet 4 of4 3,924,622

FIGURE 6 ZERO-ORDER RELEASE METHOD CROSS REFERENCE TO RELATEDAPPLICATION This application is a continuation-in-part of my copendingapplication Ser. No. 405,616, filed Oct. 11, 1973, now US. Pat. No.3,851,648, patented Dec. 3, 1974.

FIELD OF THE INVENTION There is provided a method for dispensing a vaporfrom a subliming solid into a gaseous medium or a solid solute into aliquid medium at a constant rate during a prolonged period of time. Themethod may be embodied in a medicator such as a surgical implant,tampon, suppository, intrauterine device, or intravaginal device fordelivery of a drug or growth regulating substance into the system of aliving organism, or for other uses such as water or air treatment.

SUMMARY OF THE PRIOR ART Certain pesticides are sublimable solids andvarious devices have been used for delivery of the vapor thereof, suchas decorative cannisters, pet collars, etc., to the locale to betreated. Moth proofing and insecticidal agents have been delivered inthis fashion. Various means have been used for the delivery of drugs andother biologically active substances to the mammalian body by means ofspecifically fabricated tablets, implants, intrauterine devices, ocularinserts, catheter tubes, etc. which were designed to release the activesubstance at a predetermined rate. Examples of such devices areillustrated in the following patents. Levesque, US. Pat. No. 2,987,445patented June 6, 1961; Long and Volkman, US Pat. No. 3,279,996 patentedOct. 18, 1966; Rudel, US. Pat. No. 3,656,483 patented Apr. 18, 1972;Jacobs, US. Pat. No. 3,113,076 patented Dec. 3, 1963; Stephenson, etal., US. Pat. No. 3,146,169 patented Aug. 25, 1964; and Wepaic, US. Pat.No. 3,598,127 patented Aug. 10, 1971.

SUMMARY OF THE INVENTION The method employs a device comprised of acontainer of rigid material which is impermeable to the fluid mediuminto which it is desired to dispense a diffusible solid which iscontained within the device. The container may be of any convenient sizeand shape to fit the particular application under consideration. Housedwithin the container is a cavity communicating through a slot in thesurface of the container with the exterior medium through which thecontained solid is dispensed. The solid is dispensed by the processes ofdissolution or vaporization within the container into the fluid mediumwhich enters through the slot, and diffusion of the dissolved orvaporized solidoutwardly through the slot into the surrounding medium.Zeroorder release results from the configuration of the cavity and slotwhich is such as to provide an increasing surface area of diffusiblesolid exposed to the fluid medium within the container as the length ofthe path through which the dissolved or sublimed solid must diffuse toreach the exterior increases. A constant ratio of area of dissolution orsublimation surface to diffusion distance is maintained. The device isapplicable to various drug delivery systems, and to nonmedical uses suchas the dispensing of insecticides, pesticides, perfumes, and watertreatment with germ icides in swimming pools, toilets, etc.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a perspective view of adevice for use in the present process which is cylindrical in form andcontains a rectangular slot lengthwise on one side thereof whichcommunicates with a cavity within the cylindrical container thecross-section of which is shaped like a slice of pie.

FIG. 2 is a view in cross-section of the device of FIG. 1 along line 22showing the drug partially filling the cavity.

FIG. 3 is a perspective view of a device for use in the present processin which the container is ring-shaped and the diffusion slot is arrangedconcentrically upon the upper surface thereof.

FIG. 4 is a view in cross-section of the device shown in FIG. 3 alongline .4-4.

FIG. 5 is a collection of graphs in which the rate of release of adiffusible solid from the device of FIG. 1 is related to its solubility,and the dimensions of the cavity and the slot. 4

FIG. 6 is a perspective view of a device for use in the present processwhich is comprised of a hollow container in the form of a right circularcylinder bisected along the axis thereof and having an elongated.diffusion slot located on the bisecting surface along the axis.

DETAILED DESCRIPTION OF THE INVENTION In FIG. 1, the cavity 15 isillustrated by broken lines and the slot through which it communicateswith the exterior is indicated by 20. The slot is of uniform length andwidth. The narrower dimension or width is situated at the ends 21 and 24of the slot. The elongated dimension is located at the sides of the slotrepresented by 22 and 23. Drug substance or other active ingredient tobe dispensed 25 is contained within cavity 15 and is outlined by abroken line in the drawing. The cavity fill should be a solid underambient conditions. The end walls of cavity 15 are represented by 30 and31. End walls 30 and 31 lie in parallel planes which are at right anglesto slot 20, adjacent to the ends thereof, and are congruent in shape.The side edges of end walls 30 and 31 of cavity 15 are represented by32, 33, 34, and 35. They are of equal length and are arranged radiallyand inwardly divergent with respect to slot 20 so that end walls 30 and31 are pie-shaped in the embodiment shown. Also, the rear wall 40 ofcavity 15 is arcuate in contour defining a portion of the wall of aphantom cylinder whose axis lies substantially within slot 20 and theside edges 32, 33, 34, and 35 of end walls 30 and 31 are substantiallyradii of the phantom cylinder. The side walls 45 and 46 of cavity 15 aresituated adjacent opposite sides 22 and 23 of slot 20 and in radialrelation to said slot. They are congruent in shape.

FIG. 2 is a cross-section of the device of FIG. 1 taken along line 22 ofFIG. 1 in a plane parallel with the planes of end walls 30 and 31 ofcavity 15. Like numbers in FIG. 2 refer to like features of FIG. 1.Cavity 15 of the device shown in FIGS. 1 and 2 is only partially filledwith drug substance 25, 26 representing the surface of drug substance 25which is opposite slot 20.

Cavity 15 houses drug substance 25 in sealed relation to side walls 45and 46 and end walls 30 and 31 thereof. By sealed relation is meant inclose contact so that fluid medium 50 and 51 which surrounds container10 and which fills the void portion of cavity 15 cannot seep between theside walls or the end walls ofsaid cavity and the drug substance 25. Inthis fashion only one surface 3 26 of drug substance 25 is exposed tofluid medium 51 within cavity 15.

The release of drug 25 from carrier is controlled by dissolution anddiffusion processes. This includes dissolution of drug 25 into fluidmedium 51 at surface 26 thereof, and diffusion therefrom in solution toslot 20 and thence into the surrounding medium 50. The release rate ofdrug 25 through slot 20 into the surrounding medium 50 is a function notonly of the solubility and diffusion coefficient of the drug in thereceiving fluid 50 but also of the dimensions of slot 20 and of theangle between side walls 45 and 46 of cavity 15. Initially cavity may befilled flush with slot with a single pellet of drug substance 25. As thedrug is dissolved and diffused from the carrier, fluid 50 from thesurrounding medium diffuses into the cavity as shown by 51 in FIG. 2 toreplace the drug which has dissolved and diffused out.

FIG. 2 represents the cross-section of a carrier from which about 50percent of the initial drug fill has been released. The arcuate drugsurface 26 shown in FIG. 2 is naturally formed as a result of thedissolution and diffusion processes. If it is desired to prepare a drugcarrier which is only partially filled with drug substance at the outsetas shown in FIG. 2, then the surface of the drug substance should beprovided with an arcuate contour as shown at 26 in FIG. 2.

The reason for the arcuate contour of drug surface 26 is that the rateof diffusion of drug substance through medium 51 to slot 20 is inverselyproportional to the distance d separating drug surface 26 from slot 20and directly proportional to the area A of drug surface 26. The ratio ofA to d remains constant so long as slot 20 lies along the axis of asection of a cylindrical surface 26 formed by drug substance 25. Therate of release R of drug substance 25 from slot 20 is governed by theexpression shown in Equation I.

Equation I In Equation I, 6 is the angle (expressed in radians, 1 radian57.3) between side walls and 46 of cavity 15. D is the diffusioncoefficient of drug 25 in medium 50 and C, is the solubility thereof.The symbol a is the width of slot 20 and L is the length of slot 20. Thesymbol h is the distance from slot 20 to that closest hypothetical pointin medium 50 where the concentration of drug substance 25 is zero. As apractical matter, for solids with relatively low solubilities or vaporpressures a negligible or substantially zero concentration is reached ata relatively short distance from slot 20. The values for D and h for aspecific drug substance may be determined by the method of Roseman andI-Iiguchi, J. Pharm. Sci., 59, 353 (1970). For release of theprogestational steroid medroxyprogesterone acetate to vaginal tissues,they have calculated the values D=O.6 cm /day and h=0.058 cm.

The mathematical relationship of Equation I shows that since a, L, and 9are fixed by the dimensions of cavity 15, then the rate of release Rdepends upon D,.h, and Cs, all constants for any specific drugsubstance. Thus as long as drug is present and the arcuate surface 26thereof is exposed to medium 51, the rate of release will be constant.The mathematical relationship of Equation I further dictates that anincrease in L will cause a proportionate increase in the release rate R.An increase in a will cause an increase in rate R but as a is madelarger, its influence on rate declines. The rate R can be increased byincreasing .9 but like a and unlike L the effect is not linear. For aseries of related drug materials having similar diffusion constants Dand values h, the release rates of the various materials from deviceshaving the same dimensions are substantially proportional to theirsolubilities Cs. If the values for D and h have not been previouslydetermined as above, a trial and error approach to construction of thedevice to provide the desired release rate may be used.

It is preferred that rear wall 40 of cavity 15 have arcuateconfiguration as shown in FIGS. 1 and 2 similar to that of drug surface26 such that rear wall 40 forms the wall of a cylinder the axis of whichlies within slot 20. In this circumstance a steady state of release ofdrug substance 25 will be maintained until the drug is entirelyexhausted from the device. When rear wall 40 is flat or has anotherconfiguration other than the arcuate form shown, a constant rate of drugrelease will be maintained only until drug surface 26 intercepts wall 40and exposes a portion thereof. From that time until all of the drug isexhausted, the release rate R from slot 20 will be less than the steadystate zero-order condition. This may not pose a serious problem in somecircumstances, and accordingly, the configuration of rear wall 40 is notlimited in this invention to the arcuate form shown. Only drug surface26 is required to be arcuate in form to provide zero-order release afterdissolution and diffusion processes under operating conditions havereached equilibrium.

FIG. 3 illustrates another embodiment of the invention comprising anintravaginal ring 55 having an overall outside diameter of 6 or 7centimeters and a crosssectional diameter of about I centimeter. Thering serves as a container corresponding to 10 of FIG. 1 which houses acavity shown by broken lines in FIG. 3 corresponding to cavity 15 ofFIG. 1. Cavity 60 communicates with fluid medium 50 on the exterior ofring 55 through a slot in the side thereof. Slot 65 in the deviceillustrated lies circumferentially on the uppermost surface of ring 55.FIG. 4 is a cross-section of the intravaginal ring shown in FIG. 3 alongline 4-4. This illustrates the configuration of the slot and cavityalong the uppermost surface of the ring in concentric 'position. In thisinstance, the length L of slot 65 corresponds to the circumference ofthe slot. In the configuration shown with the slot along the uppersurface, a steady state of release is achieved by dissolution anddiffusion of drug substance 70, shown in FIG. 4 by the hashed mark area,since the length of exposed drug surface remains constant and equal toL. If the slot were placed on the outer or the inner surfaces of theintravaginal ring the exposed drug surface would decrease or increaserespectively as drug substance diffused from cavity 60 resulting in aslightly decreasing or increasing rate of release. A still furtherembodiment of the intravaginal ringnot shown involves a ring similar tothat of FIG. 3 with multiple cavities to provide for still higher ratesof drug release, or for drugs having very low solubilities.

Referring again to FIG. 1, drug substance 25 may be filled intoCavity'lS in the molten state and then permitted to solidify. This isparticularly suitable if the drug substance is stable at its meltingpoint and solidifies in a form such that the dissolution properties areisotropic. A compressed solid may also be used as cavity fill. Anothermeans of using the device of the present invention is to fill cavitywith a suspension of drug substance in a thixotropic gel or liquidmonomer. In the latter instance, the monomer is caused to polymerize inplace. In the former, a firm gel forms on allowing the fill to stand inthe quiescent state. So long as the drug substance diffuses through thepolymer or gel matrix and the matrix is insoluble in the liquid mediumin which the device is immersed, a steady state of release of drugsubstance through the diffusion slot will be achieved. In this instance,the diffusion coefficient of the drug substance through the polymer orgel matrix and the partitioning of drug between matrix and fluid istaken into account in calculating the release rate. In some instances,the release rate may be greater under these circumstances than when asolid pellet of drug substance is used as illustrated in FIG. 1.

FIG. 6 is a drawing of another embodiment of the invention in which thecontainer 75 is in the form of a right circular cylinder which isbisected lengthwise by a plane in which the axis of the cylinder lies.The planar bisecting face is represented by the numeral 80. Diffusionslot 85 lies along the axis of the bisected cylinder on the planar faceof the container. The inner side of the arcuate cylinder wall 81constitutes the rear wall of cavity 90 which is the interior of thecontainer. Rear wall 81 thus has the arcuate concave configuration as ispreferred for zero-order release during the entire residence time of thediffusible solid within the container while it is immersed in the mediuminto which it is desired to dispense the solid. End walls 82 and 83 arecongruent and positioned adjacent the ends of slot 85 and at rightangles thereto as is required. The portions of planar bisecting face 80of container 75 on either side of slot 85 comprise the two side walls ofcavity 90 corresponding to side walls 45 and 46 of cavity 15 of thedevice pictured in FIG. 1. In this instance, the angle 6 between theside walls is 180. Other embodiments of the invention may be constructedwith an angle 6 from about to about 270. In such instance, the cavity isformed as in FIG. 6 in the shape of a segment of a right circularcylinder having the diffusion slot located along the axis.

For the cylindrical device of FIG. 1, having diffusion slot 20 on theside thereof, the angle 9 between side walls 45 and 46 of cavity 15 mayvary from about 30 to about 140. The angle employed is selected toafford the desired release rate. The cavity of maximum volume, and thusgreatest total diffusible solid capacity, which can be constructedwithin a cylindrical device of the type shown in FIG. 1 has an angle 9of 1.36 radians or 78. The foregoing is determined by geometricconsiderations.

Substances having a wide range of solubilties or vapor pressures may bedispensed by the device of the present invention. By the use of anintravaginal ring similar to that shown in FIG. 3, a release rate of 50mcg./day of a steroid or other substance having a solubility of as lowas l.7 meg/ml. may be achieved. For an intrauterine device embodying acontainer as pictured in FIG. 1, the same release rate can be assuredfor substances having solubilities of up to about 570 meg/ml. Substanceshaving this full range of solubilities may be dispensed with devices ofthe type shown in FIG. 6. Release rates can be further manipulated bythe use of wax, polymer, or gel matrices such as petroleum wax,cholesterol, silicone rubber, polymeric hydrophilic hydrogels, andthixotropic gels prepared from polyethylene glycol,carboxymethylcellulose, or carboxyvinyl polymer as the continuous-phaseof a suspension of crystalline diffusible solid to be dispensed withinthe cavity.

DESCRIPTION OF SPECIFIC EMBODIMENTS I FIG. 5 is a collection of graphsin which the rate of release R expressed in micrograms per day isplotted as ordinate and solubility Cs in micrograms per milliliter isplotted as abscissa for delivery of a drug substance from a cylindricalintrauterine device similar to that of FIG. 1 having radius 0.12 cm andslot length 3.2 cm. Each of the lines plotted on these coordinates isfor a different device having the values for the angle 6 and slot widtha shown at the right hand side of the graph. The values of Roseman andHiguchi loc. cit.) for medroxyprogesterone acetate of D=O.6 cm lday andh=0.05 8 cm were used for these calculations. For drug substances havingsimilar D and h values and solubilities of the order of 100 microgramsper milliliter release rates upwards of 100 micrograms per day may beachieved. Medroxyprogesterone acetate has a solubility of 3.25 mcg/ml(Roseman and Higuchi, loc. cit.) and release rates of from about 2.5 to6 meg/day can, therefore, be achieved with the devices referred to inFIG. 5. Thus by reference to FIG. 5, various release rates can beachieved for a drug of given solubility by selection of the appropriateangle 9 and slot width a.

Experimental The system was tested experimentally by measuring theamount of stearic acid released from a device fabricated from stainlesssteel and immersed in USP alcohol. The prism-shaped device was 2.5inches long, 1.0 inches wide at the base, and 0.63 inches high from thebase to the slot. The sides, base, and one end were made of 18 gaugestainless steel. The other end was cut from 3/ 16th inch stainless steeland was drilled to provide a filling port which could be closed with astainless steel bolt. All of the joints were silver soldered. A largerfilling port was made in the base of the prism-like device by cutting ahole of appropriate size and soldering in place a stainless steel nut tobe closed with a stainless steel bolt. Solvent resistent gaskets wereused at both filling ports. The slot width (a) was 0.030 inches and theeffective slot length (L) was 2.263 inches. The angle 9 was For filling,the slot was covered with a sheet of polyethylene and the device wasinverted. Molten stearic acid was added through the large port inincrements. The device was rocked back and forth and the portionsallowed to solidify after each addition. The device held approximately9.5 g. of stearic acid. After the port was closed, the polyethylene wascarefully removed from the slot.

The release of stearic acid from the device into USP alcohol wasmeasured by placing the device in the bottom of a double-walled beakerwith an inside diameter of 11.0 cm. containing 1,000 ml. of alcohol. Thebolt used to close the port in the base served as a pedestal for thedevice. The beaker was kept at 30C. and its contents were stirred with athree bladed propeller (radius 2 cm., blade pitch 30) rotated at 50 rpm2.5 cm. below the solvent surface. The distance between the top of thedevice and the propeller was 4.9 cm. A cover with a hole for the stirrerand one for the sampling port was kept on the beaker.

Solvent samples were withdrawn periodically. Alcohol at 30C. was addedto the beaker to maintain volume. The stearic acid concentration in thesamples was estimated colorimetrically after extraction from the sample.A 10 ml. aliquot of the ethanolic solution containing stearic acid wasremoved from the beaker and placed in a separatory funnel. A 50 ml.volume of aqueous 0.01 M pH 7.0 phosphate buffer. containing 0.1%methylene blue (USP grade) and ml. of redistilled reagent gradechloroform were added. When a 5 ml. sample was used, an additional 5 ml.of alcohol was added to it. The separatory funnel was shaken and thelayers were allowed to separate. A 5 ml. portion of the chloroform layerwas diluted to 100 ml. with methanol and the density of blue color wasestimated photometrically at 640 nm against an appropriate standard. Theblue color was stable after approximately minutes. The absorbance waslinearly dependent on the concentration of stearic acid in the sample.The complete data 8 The following compositions illustrate cavity fillsolids for use in the present invention comprising dispersions ofsteroid compounds in solid matrices of various types.

Composition 1. Wax Matrix. White Wax, USP Megestrol Acetate, microfinefor three trials according to this procedure are listed in 20 ployed inComposition 1 may be varied, and the white Table I. wax may besubstituted by cholesterol.

TABLE I RELEASE OF STEARIC ACID FROM ZERO-ORDER DEVICE Trial I Trial 11Trail 111 Time Released Time Released Time Released 16 hr. 118 mg. 2 hr.72.6 mg. 19 hr. 263 mg.

236 mg. 24 hr. 378 mg. 26.5 hr. 272 mg. 24 hr. 41 hr. 524 mg. 31 hr. 306mg. 43 hr. 436 mg. 48 hr. 541 mg. 48 hr. 609 mg. 51 hr. 570 mg. 64 hr.721 mg. hr. 748 mg. 67 hr. 801 mg. 67 hr. 779 mg. 72 hr. 977 mg. 75 hr.902 mg. 72 hr. 813 mg. 79.5 hr. 947 mg. 94.5 hr. 1110 mg. 89 hr. 1000mg. 102.8 hr. 1360 mg. 95.5 hr. 1010 mg. 91 hr. 1230 mg. 103.5 hr. 1420mg. 114 hr. 1600 mg. 93 hr. 1070 mg. 129.5 hr. 1840 mg. l 15 hr. 1600mg. 96 hr. 1150 mg. 130.5 hr. 1810 mg. 128 hr. 1770 mg. 118.5 hr. 1310mg. 143 hr. 2000 mg. 134 hr. 1780 mg. 119.5 hr. 1310 mg. 151 hr. 2070mg. 151 hr. 2090 mg. 137.5 hr. 1590 mg. 167 hr. 2450 mg. 158 hr. 2130mg. 138.5 hr. 1600 mg. hr. 2360 mg. 161.5 hr. 1850 mg. 182 hr. 2440 mg.168 hr. 1870 mg. 199 hr. 2680 mg. 184.5 hr. 2100 mg. 206 hr. 2760 mg.192 hr. 2170 mg. 223 hr. 2990 mg. 207.5 hr. 2400 mg. 230.5 hr. 3180 mg.216 hr. 2350 mg. 247.5 hr. 3360 mg. 232.5 hr. 2860 mg. 248.5 hr. 31.20mg. 235 hr. 2830 mg. 270 hr. 2490 mg. 240 hr. 2810 mg. 271 hr. 3440 mg.257 hr. 2870 mg. 282.5 hr. 3500 mg. 261 hr. 3210 mg. 285.5 hr. 3640 mg.265 hr. 3350 mg. 290 hr. 3780 mg. 285 hr. 3620 mg. 307 hr. 3930 mg.285.5 hr. 3610 mg. 314 hr. 3860 mg. 313.8 hr. 4010 mg. 331 hr. 4090 mg.314.8 hr. 4070 mg. 330 hr. 4240 mg.

The linear regression analysis for each trial is summarized in Table II.The coefficient of determination (r was 0.99 in each case indicatingthat the data for the 55 release rate are zero-order.

Composition 2. Silicon Rubber Matrix. Silicone rubber elastomer(viscosity 35000-70000 cps.; sp. gr. (25C) 1.13 i 0.03) MegestrolAcetate, microfine 0.1 g. Stannous octanoate catalyst 0.05 g. (tincontent 2 26%) TABLE II SUMMARY OF REGRESSION ANALYSIS ON EACH TRIAL ANDON COMPOSITE OF ALL DATA Trial Trial Trial Composite 1 11 III DataRelease Rate, mg./hr. 12.73 14.24 12.89 12.72 SD (slope), mg./hr. 0.230.41 0.24 0.18 r 0.990 0.990 0.991 0.985 Intercept, mg. l 2.7 48.3 +74.221.9

SD (intercept), mg. 44.5 41.3 47.2 33.1 N 32 14 30 76 Composition 3.Carboxypolymethylene Gel.

Active ingredient, microfine 2 toll%- Sorbitol solution, USP 40% Dioctylsodium sulfosuccinate 0.02% Carbox ypolymethylene 1.2% Thiomerosol0.004% Sodium hydroxide, q.s. pH 6.5 Water qs 100.0 ml.

Composition 4. Carboxymethylcellulose Gel.

Active ingredient, microfine 2 to l0% Carboxymethylcellulose 3.5%Glycerin 8.0% Polysorbate 80 USP 0.l% Methyl paraben 0.2% Water qs 100.0ml.

Composition 5. Polyethylene Glycol Gel.

Active ingredient, microfine 2 to Polyethylene glycol 4000 10%Methylcellulose USP, 4000 cps 0.3% Water qs 100.0 ml.

In those instances wherein the diffusible solid is dissolved orsuspended in a liquid medium and filled into the container and themedium then solidified in situ to a solid matrix, a solidified matrix isselected which is insoluble in the external fluid medium into which itis desired to deliver the diffusible substance and which is permeable todiffusion of the substance or drug to be delivered. The rate of releaseof the diffusible active ingredient in this instance is described on thebasis of the same considerations and by the same formula shown above inEquation I but the diffusion constant of the diffusible substancethrough the solid matrix, referred.

to as D,,,, and the partition coefficient of the diffusible solidbetween the solid matrix and the liquid external medium into which it isto be delivered, referred to as K, also affect the rate of release ofthe diffusible substance. Equation II is a modification of Equation I inwhich these factors are taken into account R: D l h D K 9 1:

Equation II 0.6 cm. /d, D to be 0.0035 cm, /d, and K to be 260. Thesevalues for K'and D are based upon experimental measurements employing asilicone rubber matrix prepared by polymerization in situ of a siliconeelastomeric composition such as is illustrated in Composition 2 hereof.When the factor is less than 1, the rate of release would be greaterwhen the diffusible agent is dispersed in a silicone rubber matrix thanwhen the pure drug is used to fill the cavity of the carrier device.

When an aqueous thixotropic gel is used as a solid matrix in a devicesuch as shown in FIG. 1, the rate of release is; comparable to that of asimple device filled with the pure drug when a gellingagent is selectedwhich does not bind or otherwise influence dissolution ordiffusion ofthe solid to be delivered, and when an aqueous gel'having a compositionsubstantially similar to the surrounding liquid medium is used todeliver the diffusible solid.

What is claimed is:

1. Method for the automatic release at a desired substantially constantpredetermined rate R of a difiusible solid into a fluid medium intowhich said solid has a propensity to diffuse wherein said solid hasdiffusion constant (D) and solubility (C with respect to said mediumwhich comprises l. introducing said solid into a cavity within acontainer, said container being impervious to said solid and said mediumduring the period of delivery of said solid and having a slot-like porthaving uniform length and width and having two ends and two sides withthe narrower dimension (a) at the ends and the longer dimension (L) atthe sides, said port communicating in its entirety with said cavity,said cavity being defined by a rear wall, and a pair of parallelcongruent planar end walls arranged at right angles to said slot andadjacent to the ends thereof, and a pair of inwardly extending congruentplanar side walls adjacent the opposite sides of said slot and insubstantially divergent radial relation to said slot and extending tosaid rear wall, said introduction being carried out so as to completelycover the rear wall of said cavity with said solid and seal said solidto the walls thereof, and expose a single surface thereof to theslot-like port in facing relation thereto for contact with said medium,and

2. immersing said container into said medium so that the medium entersthe slot and contacts said exposed surface of said solid, and

3. adjusting the dimensions (a), (L), and (9), wherein (9) is the anglesubtended by the side walls of said cavity, so that said rate R isachieved and is defined by the expression 1 1 formed into an arcuateconcave configuration defining a segment of a cylinder wall the axis ofwhich lies within said slot 4. The method of claim 1 wherein said solidis introduced into said container to form therein a uniform dispersionthereof in a solid matrix, said matrix being insoluble in said fluidmedium and permeable to said 5. The method of claim 4 wherein prior tointroduction said matrix is in the liquid state, said solid beingdissolved or uniformly suspended therein and after said introduction theliquid matrix is solidified.

6. The method of claim 5 wherein said matrix prior to introduction ismolten and said method is carried out at a temperature lower than thesolidification temperature of said matrix.

7. The method of claim 6 wherein said matrix is white wax, USP. 7

8. The method of claim 5 wherein said liquid matrix is a polymerizablecomposition, and solidification is accomplished by polymerizationthereof.

9. The method of claim 8 wherein said polymerizable compositioncomprises a silicone rubber elastomer.

10. The method of claim 5 wherein said matrix is a thixotropic gel.

11. The method of claim 10 wherein said thixotropic gel is an aqueouscomposition containing a gelling agent selected from the groupconsisting of carboxypolymethylene, carboxymethylcellulose, andpolyethylene glycol.

1. Method for the automatic release at a desired substantially constantpredetermined rate R of a diffusible solid into a fluid medium intowhich said solid has a propensity to diffuse wherein said solid hasdiffusion constant (D) and solubility (Cs) with respect to said mediumwhich comprises
 1. introducing said solid into a cavity within acontainer, said container being impervious to said solid and said mediumduring the period of delivery of said solid and having a slot-like porthaving uniform length and width and having two ends and two sides withthe narrower dimension (a) at the ends and the longer dimension (L) atthe sides, said port communicating in its entirety with said cavity,said cavity being defined by a rear wall, and a pair of parallelcongruent planar end walls arranged at right angles to said slot andadjacent to the ends thereof, and a pair of inwardly extending congruentplanar side walls adjacent the opposite sides of said slot and insubstantially divergent radial relation to said slot and extending tosaid rear wall, said introduction being carried out so as to completelycover the rear wall of said cavity with said solid and seal said solidto the walls thereof, and expose a single surface thereof to theslot-like port in facing relation thereto for contact with said medium,and
 2. immersing said container into said medium so that the mediumenters the slot and contacts said exposed surface of said solid, and 3.adjusting the dimensions (a), (L), and ( Theta ), wherein ( Theta ) isthe angle subtended by the side walls of said cavity, so that said rateR is achieved and is defined by the expression
 2. immersing saidcontainer into said medium so that the medium enters the slot andcontacts said exposed surface of said solid, and
 2. The method of claim1 wherein said solid is introduced into said container in the moltenstate and permitted to solidify therein.
 3. The method of claim 1wherein the exposed surface of said solid for contact with said mediumis formed into an arcuate concave configuration defining a segment of acylinder wall the axis of which lies within said slot.
 3. adjusting thedimensions (a), (L), and ( Theta ), wherein ( Theta ) is the anglesubtended by the side walls of said cavity, so that said rate R isachieved and is defined by the expression
 4. The method of claim 1wherein said solid is introduced into said container to form therein auniform dispersion thereof in a solid matrix, said matrix beinginsoluble in said fluid medium and permeable to said solid, said matrixbeing characterized by diffusion constant (Dm) and partition coefficient(K) relative to said solid and said fluid medium, and suitably adjustingsaid angle ( Theta ), slot length (L), slot width (a), matrix diffusionconstant (Dm), and matrix partition coefficient (K) to achieve thedesired release rate (R) of the solid through the slot, said rate beingdefined by the expression
 5. The method of claim 4 wherein prior tointroduction said matrix is in the liquid state, said solid beingdissolved or uniformly suspended therein and after said introduction theliquid matrix is solidified.
 6. The method of claim 5 wherein saidmatrix prior to introduction is molten and said method is carried out ata temperature lower than the solidification temperature of said matrix.7. The method of claim 6 wherein said matrix is white wax, USP.
 8. Themethod of claim 5 wherein said liquid matrix is a polymerizablecomposition, and solidifiCation is accomplished by polymerizationthereof.
 9. The method of claim 8 wherein said polymerizable compositioncomprises a silicone rubber elastomer.
 10. The method of claim 5 whereinsaid matrix is a thixotropic gel.
 11. The method of claim 10 whereinsaid thixotropic gel is an aqueous composition containing a gellingagent selected from the group consisting of carboxypolymethylene,carboxymethylcellulose, and polyethylene glycol.